Antioxidant action of the antiarrhythmic drug mexiletine in brain membranes

Mexiletine is a class Ib antiarrhythmic drug used in the treatment of ventr icular arrhythmias. The Naf channel blocker mexiletine inhibits calcium inf lux in cells via decreasing reverse operation of the Na+-Ca2+ exchanger. Th us this drug is shown to protect the CNS white matter against anoxic/ischem ic injury. The aim of our study was to investigate if this drug could act a s an antioxidant drug as well. The antioxidant action of this drug was stud ied under different oxidant conditions in vitro, and thiobarbituric acid-re active substances were measured to follow lipid peroxidation. Mexiletine in hibited iron-ascorbate-H2O2-induced lipid peroxidation in brain membranes, liver microsomes and phospholipid liposomes, being most effective in brain membranes. The inhibition was dose- and time-dependent. Mexiletine also inh ibited copper-ascorbate-H2O2 -induced lipid peroxidation but to a lesser ex tent. It is concluded that mexiletine has a dual effect toward oxidative in jury in brain, both by inhibiting Na+-Ca2+ exchanger-dependent Ca2+ influx and by acting as an inhibitor of lipid peroxidation. However, as this drug is effective at millimolar concentrations, it should be considered less act ive than natural antioxidants that are effective at micromolar concentratio ns.